On Intrahelical Hydrogen Bonding and Stability of β‐Helices: The behavior of some D,L‐alternating oligoleucines with an N‐methylated residue

Abstract

An N-methylated residue at the n -3 position of the chain was used to reduce the maximum number of H-bonds realizable by some D,L-alternating oligopeptides ing4 '-, TtB5 '-and Tl/rs 6-helices and thus increase for the oligopeptides, the relative stability of largerb -helices. With D,L-alternating oligoleucines of the series Boc-Leu,-OMe, however, this approach did not produce the helices expected. Although tl/r"-helices with only one free NH per strand would theoretically be possible, the N-methylated oligoleucines formed instead flawed g4 4-helices having three free NH's in CHCI, as well as in other solvents of low polarity. These observations confirm that the stability ofg-helices does not depend only on the number of intra-or interstrand H-bonds, and corroborate the idea thatg -helices with large cavities are inherently unstable.

Conformational and structural analysis of the equilibrium between single‐ and double‐strand β‐helix of a D,L‐alternating oligonorleucine

“…Anhydrous formic acid (6 mL) was added to 200 mg (156 mol) Boc-XMe-OMe, and the solution was stirred at 50°C for 1 h. After cooling the solution to room temperature, 2 mL acetic anhydride was added and stirring was continued for 3 h. The crude product was isolated by evaporation and dissolved in 40 mL CHCl 3 . This solution was washed with 0.5 N Na 2 CO 3, then with water, and finally dried over MgSO 4 .…”

“…The analysis of the amide proton chemical shift is particularly interesting since a ␦ HN value higher than 7 ppm indicates that the amide proton is involved in a H-bond. 3,32,33 From Table I it can be deduced that only the HN of residue 9 does not form a H-bond in the main conformation. For the second conformation, it can be inferred that residues 2, 4, and 9 are not involved in a H-bond (Table II).…”

“…The N-methylation constrains the number of possible conformations that the peptide can adopt since this substitution interfere with the intra-or interchain H-bond formation. 3 In our previous work, the structure of two D,L alternating oligonorleucines with Boc-(tert-butyloxycarbonyl) and MeO-end groups has been determined. 5,6 One-dimensional (1D) and two-dimensional (2D) NMR data for Boc-XIIMe-OMe oligopeptide clearly point to a simple right-handed ␤ 4.4 -helix conformation in chloroform.…”

“…In recent years various linear stereo-co-oligopeptides with a regularly alternating sequence of D and L residues along the backbone chain have received considerable attention [1][2][3] because they are able to assume several kinds of regular helical conformations, ␤-helices. For instance, this is the case of gramicidin A linear polypeptide antibiotic synthesized by Bacillus brevis.…”

“…The norleucine is a synthetic lineal amino acid soluble in apolar solvents that reduces the conformational effects of the side chain due to steric repulsions. 3 All these oligopeptides have been N-methylated in the (n Ϫ 3) residue from the N-terminal (where n is the number of residues in each peptide). The N-methylation constrains the number of possible conformations that the peptide can adopt since this substitution interfere with the intra-or interchain H-bond formation.…”